The objective of this research proposal is to continue the collaborative activities of an established program project, involving five multidisciplinary research groups. These groups share clinical, biochemical, cellular and molecular biological knowledge to elucidate: (1) the molecular mechanisms of inborn errors of metabolism and environmental events associated with mental retardation (Projects I, II, and IV); (2) gene regulation (Projects I, II, III, V, and VI); (3) brain development and differentiation (Projects II, III, V, and VI); (4) metabolism of the brain and its component cell types (Projects I, II, and IV); and (5) signalling between different brain cells (Projects II, III, and V). These projects continue the emphasis on the neurobiological aspects of mental retardation and developmental disabilities. The investigators share: cell culture systems, molecular biology approaches, in vitro mutagenesis, gene transfer and transgenic animals. We expect this highly integrated and multidisciplinary program to provide major advancements in our understanding of the normal and abnormal development of neurons and glial cells. A major research effort is directed at elucidating the molecular mechanisms of oligodendrocyte differentiation in relation to its two known major functions: myelination and iron metabolism (Projects II, III, IV and V). All projects address the question of the influence of genes and the environment on development. The effort should lead to the development of concepts for specific therapeutic treatments for numerous CNS developmental disorders. In addition, this multidisciplinary program will provide a rich environment for the research training of graduate students and postdoctoral fellows.